Vistas in Non-Small Cell Lung Cancer (NSCLC) Treatment: of Kinome and Signaling Networks

Abstract

Non-small cell lung cancer (NSCLC) is the prevailing lung cancer type, accounting for ~85% of all lung cancer cases. Despite their initial promise, current chemotherapeutic protocols are reaching their limits. This necessitates the prompt discovery of new molecular drivers and the development of novel regimens for advanced NSCLC. Herein, we pose that there is a need to systematically profile the human kinome activity of NSCLC. Using available state-of-the-art technologies, a wide gamut of kinase activities can be simultaneously mapped and quantified specifically in the primary or metastatic cancer states, with oncogenic kinase functions being likely linked to mutation signatures and malignant features of NSCLC. New chemical compound libraries can then be screened for kinase inhibitory properties in preclinical model systems, with presumptive induction of programmed cell-death subroutines and signaling-disintegration routes serving as major outputs of novel inhibitor tumor-suppressor potentials.

Keywords: Human kinome activity; Non-small cell lung cancer (NSCLC); Serine/threonine protein kinases; Signal transduction networks; Therapeutic strategies; Tyrosine protein kinases.

Figure 1

Schematic representation of signaling pathways and potential targets in NSCLC. Solid arrows denote activating protein (kinase) phosphorylation events and dashed arrows kinase crosstalk between two different signal transduction cascades. Lightning symbols indicate potential kinase targeting by specific inhibitors. R: Receptor (e.g. Tumor Necrosis Factor Receptor 1 (TNFR1)); RTK: Receptor Tyrosine Kinase (e.g. Epidermal Growth Factor Receptor (EGFR), Mesenchymal-Epithelial Transition factor (MET)); S/TPK: Serine/Threonine Protein Kinase; TyrPK: Tyrosine Protein Kinase; TF: NSCLC-implicated Transcription Factor (e.g. Activator Protein-1 (AP-1), Nuclear Factor-kappa B (NF-κB), Signal Transducer and Activator of Transcription 3 (STAT3)); S/TPKIs: Serine/Threonine Protein Kinase Inhibitors; RTKIs: Receptor Tyrosine Kinase Inhibitors; TyrPKIs: Tyrosine Protein Kinase Inhibitors. This figure was created based on the tools provided by Biorender.com (accessed on 14/03/2023).